WO2024091989A1 - Compositions stabilisées comprenant du cannabidiol - Google Patents

Compositions stabilisées comprenant du cannabidiol Download PDF

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Publication number
WO2024091989A1
WO2024091989A1 PCT/US2023/077706 US2023077706W WO2024091989A1 WO 2024091989 A1 WO2024091989 A1 WO 2024091989A1 US 2023077706 W US2023077706 W US 2023077706W WO 2024091989 A1 WO2024091989 A1 WO 2024091989A1
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composition
cancer
cbd
cannabidiol
patient
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PCT/US2023/077706
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English (en)
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Alexandra M. Capano
Pradeep Singh Tanwar
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Ecofibre USA Inc.
The University Of Newcastle
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Publication of WO2024091989A1 publication Critical patent/WO2024091989A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the inventions disclosed herein are related to delivery methods and compositions for therapeutic compositions and treatments of gynecological disorders and cancers, through administration of an effective amount of cannabis extracts and an antioxidant, alone or in combination with a chemotherapeutic agent.
  • the cannabis extracts comprise one or more cannabinoids, and specifically therapeutic amounts of cannabidiol (CBD) and often include one or more additional cannabinoid, terpene, or other molecules within the cannabis extract, functioning and as the antioxidant.
  • CBD cannabidiol
  • BACKGROUND OF THE INVENTION Women face a host of gynecological disorders for which there is currently no adequate method of treatment.
  • Cancers may infiltrate any number of cells and organs in the gynecological tract. Unfortunately, many of these cancers are aggressive and have significant risk of metastatic disease. [0004] Cancer represents the phenotypic end-point of multiple genetic lesions that endow cells with a full range of biological properties required for tumorigenesis.
  • genomic feature of many cancers including, for example, gynecological cancers such as endometrial cancer, is the presence of numerous complex chromosome structural aberrations, including translocations, intra-chromosomal inversions, point mutations, deletions, gene copy number changes, gene expression level changes, and germline mutations, among others. Whether a cancer will respond to a particular treatment option may depend on the particular genomic features present in the cancer.
  • Endometrial cancer is a type of cancer that begins in the uterus, within the layers of cells that form the lining of the uterus. EC is currently the most common cancer of the female genital tract in developed countries. The incidence of EC has continued to increase over more than 50% during the last two decades, with 66,570 new cases and 12,940 deaths recorded in 2021 in the United States alone.
  • Treatment options for EC are currently limited to surgery (hysterectomy and bilaterial salpingo-oophorectomy) followed by adjuvant therapy (chemotherapy or hormonal agents) depending on the clinical and histopathological characteristics of the disease. While primary surgical treatment is beneficial in most patients, about 15-20% of patients develop the recurrent disease even if no symptoms of advanced metastatic disease are present at the time of diagnosis. The chance of recurrence, according to the International Federal of Gynecology and Obstetrics (FIGO), is 10-20% in Stages I-II and 50- 70% in stages III-IV. [0006] Ovarian cancer is the second most common gynecologic cancer in the United States and causes more deaths than any other cancer of the female reproductive system.
  • Stage 3 cancer means that the ovarian cancer cells have spread or grown into nearby organs of the pelvis, and thus the disease is not contained within the ovaries or fallopian tubes. Because of the late stage of diagnosis, and the aggressiveness of ovarian cancer, the five-year survival rate is only approximately 39%. Current treatment options remain inadequate.
  • CBD has been suggested as a possible treatment for several different therapeutic treatments. Delivery of CBD to patients typically involves a lipid carrier as CBD is virtually insoluble in water.
  • One of the primary carriers identified in the prior art for CBD is olive oil.
  • Olive oil is readily available and palatable oil, which is compatible with CBD and hemp extracts 2 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 in general.
  • Olive oil is high in the antioxidant tocopherol which comprises a chromane ring with a hydroxyl group that can donate a hydrogen the atom.
  • WO 2020/0163775 to Alugupalli teaches a nanoemulsion as a carrier with olive oil as a carrier at up to 75% w/v of its nanoemulsion. Alugupalli specifically details the increased efficacy of the olive oil nano emulsion to a control without a carrier.
  • WO 2020/0194237 to Koren teaches the use of cannabinoids, within a carrier or as an excipient that may include cocoa butter, as well as a number of different edible oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil.
  • a further reference 17/640,473 to Goldner teaches a cannabinoid-containing additive that uses a carrier oil, and forming an oil and water emulsion to carry the cannabinoid molecules.
  • optimal oils are edible oils such as coconut oil, olive oil, soybean oil, grapeseed oil, and avocado oil.
  • Tocopherol has the following chemical structure: 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 [0013]
  • Tocopherol had anti-antiproliferative effects, meaning it rescued cancer cells from apoptosis. www.mdpi.com/1424-8247/15/3/366.
  • compositions and methods of treatment of noncancerous gynecological disorders as well as gynecological cancers and estrogen sensitive cancers, wherein cannabis extracts are combined with a flavonoid can be used alone or with concurrent therapeutic molecules, such as a chemotherapeutic agent, to increase effectiveness of the chemotherapeutic agent.
  • a composition for treatment of noncancerous gynecological disorders or gynecological cancers comprising cannabidiol at between 50 and 99.9% by weight of the composition and a flavonoid at between 0.1 and 50% by weight of the composition.
  • the composition wherein the cannabidiol is provided from a full spectrum hemp extract (FSHE), a broad spectrum hemp extract (BSHE), a CBD isolate, and cannabidiolic acid (CBDA), and combinations thereof.
  • FSHE full spectrum hemp extract
  • BSHE broad spectrum hemp extract
  • CBD isolate CBD isolate
  • CBD isolate CBD isolate
  • CBD isolate cannabidiolic acid
  • the composition wherein the cannabidiol is provided from a BSHE or FSHE, and which comprise (i) from 50% to 99.9% by weight of CBD and (ii) at least one other cannabinoid selected from ⁇ -9-tetrahydrocannabinol ( ⁇ 9-THC), 4 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), ⁇ -8-tetrahydrocannabinol ( ⁇ 8-THC), cannabichromene (CBC), cannabichromene acid (CBCA), cannabigerol (CBG), cannabigerol acid (CBGA), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cann
  • THCA tetra
  • the composition wherein at least a portion of the CBD is synthetic.
  • the composition wherein the flavonoid is a flavonol, a flavononol, or a flavone.
  • the composition wherein the flavonoid has a concentration of at least 50 ⁇ M; and more preferably at least 150 ⁇ M.
  • the composition wherein the flavonoid has the following structure: wherein attached at R3 is at least one of R5, R6, R7, R8, R2′, R3′, R4′, R5′, and R6′ is a hydroxyl.
  • composition wherein a hydroxyl group is attached at at least two of R5, R6, R7, R8, R2′, R3′, R4′, R5′, and R6′.
  • the composition wherein the flavonoid is selected from the group consisting of: myricetin, chrysin, taxifolin, galangin, quercetin, luteolin, 3-hydroxyflavone, and combinations thereof.
  • the composition where in the ratio of the cannabidiol to the flavonoid is 5 ⁇ g/mL:1 ⁇ M to 5 ⁇ g/mL:200 ⁇ M, and all ratios in between.
  • the composition further comprising a chemotherapeutic agent; preferably, wherein the chemotherapeutic agent is selected from the group consisting of: paclitaxel, carboplatin, doxorubicin, cisplatin, docetaxel, and the combined therapy of carboplatin or cisplatin with paclitaxel, altretamine, capecitabine, cyclosphosphamide, etoposide, gemcitabine, ifosfamide, itinotecan, melphalan, pemetrexed, topotecan, binorelbine, fluorouracil, methotrexate, cetuximab, and combinations thereof.
  • the chemotherapeutic agent is selected from the group consisting of: paclitaxel, carboplatin, doxorubicin, cisplatin, docetaxel, and the combined therapy of carboplatin or cisplatin with paclitaxel, altretamine, capecitabine, cyclo
  • the composition wherein the composition comprises a carrier; and the composition has a pH of between 3.5 to 6.
  • a method of treatment of a gynecological disease or disorder comprising administering to a patient in need thereof, an effective amount of a composition.
  • a composition for treatment of a gynecological disease or disorder comprising a cannabis extract and an antioxidant selected from the group consisting of a flavonol, a flavononol, and a flavone, wherein the cannabis extract is selected from the group 6 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 consisting of: a broad spectrum hemp extract, a full spectrum hemp extract, a CBD isolated, and combinations thereof; wherein each of the cannabis extracts comprises between 50 and 100% by weight of cannabidiol; and wherein the flavonoid has the structure: wherein attached at each of and R6′ is a hydrogen or a hydroxyl.
  • the composition wherein the flavonoid comprises at least two hydroxyl groups attached at R3, R5, R6, R7, R8, R2′, R3′, R4′, R5′, and R6′; and most preferably, wherein attached at R3 is a hydroxyl; and attached at at least two of R5, R6, R7, R8, R2′, R3′, R4′, R5′, and R6′are a hydroxyl; and most preferably, wherein attached at at least three of R3, R5, R6, R7, R8, R2′, R3′, R4′, R5′, and R6′ are a hydroxyl.
  • the composition wherein the ratio of the cannabis extract to the flavonoid is between 5 ⁇ g/mL:1 ⁇ M to 5 ⁇ g/mL:200 ⁇ M, and all ratios in between.
  • the composition further comprising a carrier, wherein the cannabis extract makes up between 50 and 99% by weight of the composition, and the flavonoid makes up between 0.1 and 50% by weight of the composition.
  • the composition wherein the cannabis extract is the carrier.
  • the composition further comprising a chemotherapeutic agent.
  • the composition wherein the cannabis extract comprises at least one other cannabinoid selected from ⁇ -9-tetrahydrocannabinol ( ⁇ 9-THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), 7 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 ⁇ -8-tetrahydrocannabinol ( ⁇ 8-THC), cannabichromene (CBC), cannabichromene acid (CBCA), cannabigerol (CBG), cannabigerol acid (CBGA), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabinol (CBN), cannabicyclol (CBL), and combinations thereof.
  • cannabinoid selected from ⁇ -9-tetrahydrocannabinol (
  • a method of treatment of endometrial cancer comprising administering to a patient in need thereof, an effective amount of a composition.
  • a method of treatment of ovarian cancer comprising administering to a patient in need thereof, an effective amount of a composition.
  • a method of treatment of an estrogen sensitive cancer comprising administering to a patient in need thereof, an effective amount of a composition.
  • a method of treatment of an estrogen receptor positive disease or disorder comprising administering to a patient in need thereof, an effective amount of a composition.
  • the method wherein the cannabis extract comprises cannabidiol at between 50-99.9% by weight, preferably between 60 and 99.9% by weight, more preferably between 70 and 99.9% by weight, more preferably between 80 and 99.9% by weight, and/or most preferably between 90 and 99.9% by weight.
  • the method wherein: (a) the method further comprises administration of the cannabis extract to the patient via an oral dose, oral mucosal dose, intravaginal dose, or combinations thereof; and/or (b) the method further comprises administration of a dose of the cannabis extract to the patient at least once every three days, preferably at least once a day, at least twice a day, or at least three times a day; and/or (c) the method further comprises administration of an amount of the cannabis extract sufficient to generate a concentration of at least 10 ⁇ g/mL of the cannabis extract at a target tissue in the patient, preferably wherein the target tissue is a gynecological cancerous tissue; 8 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 and/or (d) the method further comprises administration of an amount of the cannabis extract sufficient to reach an effective therapeutic level as measured through systemic plasma levels of CBD; and/
  • the method wherein: (a) the cancer has metastasized; and/or (b) the gynecological cancer is a chemoresistant cancer.
  • the method further comprises administering the cannabis extract to the patient via intravaginal administration, preferably wherein: (a) the cannabis extract comprises between 60% and 99.9% CBD; and/or (b) the cannabis extract is selected from a full spectrum hemp extract (FSHE), a broad spectrum hemp extract (BSHE), and a CBD isolate; and/or (c) the cannabis extract comprises CBDA at between 0.1 and 10% by weight.
  • the composition comprises (i) a carrier, preferably said carrier comprises an oil or fat and/or (ii) at least one terpene, at least one polyphenol, at least one essential fatty acid, at least one phytonutrient, or a combination thereof, optionally wherein the at least one terpene, at least one polyphenol, at least one essential fatty acid, at least one phytonutrient, or combination thereof make up between 1% and 50% by weight of the total weight of the composition, further optionally wherein: (a) the terpene is selected from ⁇ -myrcene, ⁇ -caryophyllene, linalool, ⁇ -pinene, citral, D-limonene, eucalyptol, and combinations thereof; and/or (b) the essential fatty acid is selected from an omega 3 acid, an omega 6 acid, an omega 9 acid, and combinations thereof; and/or (c) the phytonutrient is selected from a sterol, carotene, an sterol, carotene, an
  • the method wherein: (a) the chemotherapeutic agent is selected from paclitaxel, carboplatin, doxorubicin, cisplatin, docetaxel, and the combined therapy of carboplatin or cisplatin with paclitaxel, altretamine, capecitabine, cyclosphosphamide, etoposide, gemcitabine, ifosfamide, itinotecan, melphalan, pemetrexed, topotecan, binorelbine, fluorouracil, methotrexate, cetuximab, and combinations thereof; and/or (b) the cancer is a chemoresistant cancer; and/or (c) the method comprises a first step of determining 9 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 chemoresistance of a cancer
  • the method wherein the gynecological cancer is a grade 1, grade 2, or grade 3 cancer.
  • the method wherein a chemotherapeutic agent and composition comprising the CE and flavonoid are administered as one composition or as two different compositions.
  • a method of treating a gynecological cancer comprising: (a) taking a cancerous cell from a patient and forming an organoid from the cancerous cell; (b) performing a screen on the organoid to determine a chemotherapeutic drug capable of reducing the precent of viable organoids by 50% with an IC50 dose of the chemotherapeutic drug; and (c) administering to the patient the chemotherapeutic drug with an effective amount of a composition comprising a cannabis extract (CE) having between 50% and 99.9% by weight CBD and a flavonoid having a concentration of between 0.1 and 50% by weight.
  • CE cannabis extract
  • a method of treatment of a noncancerous gynecological disorder comprising administering to a patient in need thereof, an effective amount of a cannabis extract and an effective amount of a flavonol, having the structure: 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 wherein there is at least one hydroxyl group attached at one or more of R5, R6, R7, R8, R2′, R3′, R4′, and R5′.
  • the method wherein a hydroxyl group is positioned at R5 and R7.
  • the method wherein a hydroxyl group is positioned at R5, R7, and at least one of R3′, R4′, and R5′.
  • the method wherein the cannabis extract is selected from the group consisting of a FSHE, a BSHE, a CBD isolate, or a CBDA isolate.
  • the method wherein the cannabis extract is present at a ratio to the flavonol of between 5 ⁇ g/mL:1 ⁇ M to 5 ⁇ g/mL:200 ⁇ M, and all ratios in between.
  • the method wherein the noncancerous gynecological disorder is selected from the group consisting of ovarian endometrioma, a deep endometriosis, dysmenorrhea, fibroids, and combinations thereof.
  • the method wherein the cannabis extract further comprises cannabidiol at between 50 and 99% by weight of the CE, and at least one additional cannabinoid in a concentration of between 0.1 and 10% by weight of the CE, selected from the group consisting of ⁇ -9-tetrahydrocannabinol ( ⁇ 9 -THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), ⁇ -8-tetrahydrocannabinol ( ⁇ 8 -THC), cannabichromene (CBC), cannabichromene acid (CBCA), cannabigerol (CBG), cannabigerol acid (CBGA), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabinol (CBN), cannabicyclol (CBL), and combinations thereof.
  • ⁇ -9-tetrahydrocannabinol ⁇ 9 -THC
  • THCA
  • a method of treatment of a gynecological cancer comprising: administering to a patient in need thereof, a combined therapeutic treatment plan comprising of a chemotherapeutic agent and a composition comprising a cannabis extract and an effective amount of a flavonoid selected from the group consisting of: a flavonol, a flavononol, and a flavone.
  • the method wherein the composition is administered orally, intravaginally, oral mucosally, through the nasal mucosa, dermally, subcutaneously, or through intravenous injection.
  • the method wherein the chemotherapeutic agent is administered via the same or a different route of administration to the composition.
  • the method wherein the gynecological cancer is a grade 1, grade 2, or grade 3 cancer.
  • the method wherein the gynecological cancer is a chemoresistant gynecological cancer.
  • the method wherein the gynecological cancer is an endometrial cancer or an ovarian cancer.
  • the method wherein the composition is adjusted to an acidic pH between 3.5 and 6.
  • FIGS.1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, and 1I depict endometrial cancer cells being treated with a cannabis extract comprising CBD, with FIG.1A showing a diagram of the process of capturing the data regarding protein expression, FIG.1B depicting protein differentiation numbers; FIG.1C depicting upregulated and down regulated cells in the vehicle and with a cannabis extract comprising CBD treatment; FIG.1D depicting the top 20 up and down regulated proteins in ECC treated cells; and FIG.1E depicting the cannabis extract’s effects on signaling and trafficking of various physiological and pathophysiological pathways.
  • FIG.1F depicts the percent of patients in which CB1 receptors are implicated in progression or management of the disease
  • FIG.1G depicts the percent of patients in which Cannabinoid receptor 2 is implicated in progression or management of disease
  • FIG.1H depicts cannabinoid receptor 1 protein expression in an endometrial cancer cell
  • FIG.1I depicts cannabinoid receptor 2 protein expression in an endometrial cancer cell.
  • FIG.2 depicts the decrease in in organoid number compared to the vehicle for endometrial cancer organoids treated with different concentrations of hemp extract including 2, 3, 4, and 5 ⁇ g/mL.
  • FIGS.3A and 3B depict a grade 3 endometrial cancer organoid tested in two trials at concentrations of 2, 3, 4, 5, 7, and 10 ⁇ g/mL.
  • FIGS 4A, 4B, 4C, and 4D depict chemosensitive endometrial cancer patient derived organoids, being tested against four different cannabis extracts, namely a broad spectrum hemp extract (BSHE) (FIG.4A), a full spectrum hemp extract (FSHE) (FIG.4B), a CBD isolate (FIG. 4C) and CBDA (FIG.4D).
  • FIG.5 depicts a graphical chart of endometrial cancer tumor volumes within mice, wherein the mice were injected with patient derived endometrial cancer cells. The data shows the change in tumor volume from day 7 to day 21 and depicting the therapeutic efficacy of the various cannabis extracts on the tumor volumes.
  • FIGS.6A and 6B depict a combined therapy treatment tested on patient derived endometrial cancer organoids, wherein the chemotherapy agent is paclitaxel and is administered with a cannabis extract
  • FIG.6A is for grade 2 endometrial cancer
  • FIG.6B is grade 3 endometrial cancer.
  • FIG.7 depicts a combined therapy treatment tested on patient derived endometrial cancer organoids, wherein the chemotherapy agent is carboplatin and is administered with a cannabis extract.
  • FIG.8 depicts tumor volume data for mice administered paclitaxel and a cannabis extract, which depicts the synergy related to the combined impact of chemotherapy being combined with the cannabis extract.
  • FIG.9 depicts a chart showing the impacts of pH on therapeutic efficacy of the cannabis extracts. 13 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500
  • FIGS.10A and 10B depict a graphical overview of the response of high grade ovarian cancer organoids to low doses (FIG.10A) of 2, 3, 4, and 5 ⁇ g/mL of CBD, and FIG.10B depicting higher doses at 3, 5, 7, and 10 ⁇ g/mL doses.
  • FIGS 11A, 11B, 11C, and 11D depict results from chemosensitive and chemoresistant ovarian cancer patient derived organoids, being tested against four different cannabis extracts, namely a broad spectrum hemp extract (BSHE) (FIG.11A), a full spectrum hemp extract (FSHE) (FIG.11B), a CBD isolate (FIG.11C) and CBDA (FIG.11D).
  • FIG.12A and 12B depict ovarian cancer organoid cells and their response to paclitaxel and a combined treatment of paclitaxel and cannabis extract.
  • FIG.12A depicts chemosensitive organoids
  • FIG.12B depicts chemoresistant organoids.
  • FIGS.13A and 13B depict human head and neck cancer organoids being treated with three different cannabis extracts, namely, broad spectrum hemp extract (BSHE), full spectrum hemp extract (FSHE), and CBD isolate.
  • FIG.13A details that head and neck cancers showed a viability of about 10% or less at a concentration of 10 ⁇ g/mL for two cannabis extracts. Notably, viability at 10% or less is considered at or close to zero, because of the background noise in the assay test.
  • FIG.13B shows the use of CBDA, with concentrations at 0, 1, 5, 10, 15, 20, 25, 35, and 50 ⁇ g/mL. Again, the results between about 15 and 50 ⁇ g/mL are somewhat indistinguishable due to the sensitivity of the counting system at the lowest levels.
  • FIG.14 details head and neck cancer organoids response to paclitaxel or a combination of paclitaxel and a cannabis extract, at 4, 16, and 20 nm/ml concentration, with an IC50 dose of the cannabis extract.
  • FIGS.15A and 15B depict further graphs of BSHE, FSHE, and CBD isolate for 1, 2, 3, 4, 5, 7, and 10 ⁇ g/mL concentration on endometrial organoids
  • FIG.22B depicts a graphical depiction of response to CBDA for endometrial organoids.
  • FIG.16 depicts a graphical representation of the kill rate of flavonoids tested on endometrial cancer derived organoids, as compared to a control.
  • FIGS.17A and 17B depict a graphical representation of the kill rate of certain flavonoids being combined with BSHE.
  • FIG.18 depicts a graphical representation of the kill rate of certain flavonoids being combined with FSHE.
  • FIGS.19A, 19B and 19C depict a comparison of one flavanol across different cell types. DETAILED DESCRIPTION OF THE INVENTION [0081] As used herein, the term “about” means plus or minus 5% of the numerical value of the number with which it is being used.
  • administering when used in conjunction with a therapeutic means to administer a therapeutic directly to a subject, whereby the agent positively impacts the target.
  • administering the therapeutic drug or compound may be accomplished by, for example, injection, oral administration, topical administration, mucosal administration and/or in combination with other known techniques.
  • the administering techniques may further include heating, radiation, chemotherapy, ultrasound, and the use of delivery agents.
  • the administration is through oral, oral mucosal/sublingual, nasal mucosa, intravenous, intramuscular, dermal, intravaginal dosage forms, or other suitable forms of administration.
  • Such intravaginal forms are intended to be inserted into the vagina, typically with a carrier, wherein the active ingredients pass through the vaginal mucosal membrane.
  • the active ingredients may also be provided in an oral form, to be swallowed.
  • Another oral form is an oral mucosal application, which is often provided as a sublingual application, which, while it is ultimately swallowed to enter the stomach, is intended to be held in the mouth, for example under the tongue, and the active ingredients pass through the oral mucosal membrane before being swallowed or passed into the stomach by salivary action or active swallowing of the materials or both, and for nasal mucosa, the material is administered into the nasal passages to allow the therapeutic agents to permeate the nasal mucosa.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions of the present invention encompass any composition made by admixing a compound or compounds of the present invention and a pharmaceutically acceptable carrier.
  • agent means a compound or composition utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a patient.
  • agent active agent
  • therapeutic agent encompass a cannabis extract and/or additional agents as described in the present disclosure.
  • a “therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to inhibit, block, or reverse the activation, migration, proliferation, alteration of cellular function, and to preserve the normal function of cells.
  • compositions of the invention may be used to provide improvement in any of the conditions described. It is also contemplated that the compositions described herein may be administered to healthy subjects or individuals not exhibiting symptoms but who may be at risk of developing a particular disorder.
  • the specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances 16 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated.
  • a therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue to achieve the therapeutic response.
  • the therapeutic shall be effective in treating cancerous or noncancerous growths related to gynecological cancers, estrogen mediated diseases and cancers, and metastatic disease relating thereto.
  • treat refers to both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results.
  • beneficial or desired results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder, or disease such as a reduction in the size of a tumor; stabilization (i.e., not worsening) of the state of the condition, disorder, or disease; delay in onset or slowing of the progression of the condition, disorder, or disease; amelioration of the condition, disorder, or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder, or disease.
  • the term “cannabis extract” (CE) is a composition derived from the Cannabis genus of plants (including hemp).
  • a cannabis extract contains cannabinoids with the primary cannabinoid by weight being cannabidiol (CBD).
  • CBD cannabidiol
  • a CE may comprise, by weight, between about 1 and 100% CBD (being a refined CBD isolate), preferably between about 20 and 99.9% CBD, more preferably between about 50 and 99.9% CBD, even more preferably between about 70 and 99.9% CBD, and most preferably between about 90 and 99.9% CBD.
  • Synthetically derived CBD may make up all or a part of the percentage of CBD within a cannabis extract.
  • embodiments of CE may include at least one additional cannabinoid, typically selected from the group consisting of ⁇ 9-THC, THCA, THCV, ⁇ 8-THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL, and combinations thereof.
  • the at least one additional cannabinoid, or combinations thereof comprise by 17 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 weight between about 0.1 and 40% of the CE.
  • full spectrum hemp extract, broad spectrum hemp extract, CBD isolate, and CBDA isolate are forms of CE utilized herein, as nonlimiting examples of the CE.
  • CBD is often used interchangeably with CE, to mean the CE product containing the particular amount of CBD.
  • CBD refers to a CBD isolate, which means the CE was processed to separate CBD from virtually all other components of the CE.
  • synthetic cannabinoids means, those cannabinoid molecules that are synthetically created and not formed from an extraction of a cannabis plant.
  • full spectrum hemp extract is a composition derived from the Cannabis genus of plants which contains CBD, and quantities of THC ( ⁇ 9 -THC, THCA, THCV, ⁇ 8 -THC) above 0, preferably, between 0.01 and 5%, most preferably being between 0.01% and 0.3%.
  • the FSHE may comprise additional cannabinoids, yielding a product that comprises at least 50-99.9% CBD, at least 0.01 to 10% THC ( ⁇ 9 -THC, THCA, THCV, ⁇ 8 - THC), and total cannabinoids of between 50% and 99.9% of the weight of the CE.
  • BHSE broad spectrum hemp extract
  • a BHSE comprises between 60 and 99.9% CBD and least one additional cannabinoid, selected from the group consisting of ⁇ 9 -THC, THCA, THCV, ⁇ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL, and combinations thereof at between 0.1 and 40%.
  • a noncancerous gynecological disorder means a gynecological disorder selected from the group consisting of: endometriosis including ovarian endometrioma or deep endometriosis, dysmenorrhea, fibroids, and combinations thereof.
  • Cannabidiol has recently begun serious study for potential therapeutic effects. Applicant, however recognized that a disconnect exists in the literature regarding delivery of cannabidiol in an effective manner. Indeed, the prior art generally shows that cannabidiol is ineffective at reducing tumor size, and instead may only be sufficient to delay or reduce the growth rate of tumors or other disease states.
  • Applicant is primarily interested in diseases and 18 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 disorders related to women’s reproductive health, which include NCGD’s, gynecological cancers, and estrogen sensitive cancers. A dearth of effective treatments continues confound these diseases and their related co-morbidities.
  • An association between endometriosis and Endometrial cancer (EC) has been indirectly suggested by epidemiological, biological, and molecular studies, and recent research suggests a genetic basis for overlap.
  • EC protein tyrosine phosphatase receptor type D
  • PTPRD protein tyrosine phosphatase receptor type D
  • EC is one of the most frequently diagnosed gynecological cancers worldwide, and its prevalence has increased by more than 50% over the last two decades.
  • Endometrial cancer also called endometrial carcinoma
  • endometrial carcinoma starts in the cells of the inner lining of the uterus (the endometrium). This is the most common type of cancer in the uterus.
  • Endometrial carcinomas can be divided into different types based on how the cells look under the microscope. They include: Adenocarcinoma (most endometrial cancers are a type of adenocarcinoma called endometrioid cancer -- see below; Uterine carcinosarcoma or CS; Squamous cell carcinoma; Small cell carcinoma; Transitional carcinoma; and Serous carcinoma. Clear-cell carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, and serous adenocarcinoma are less common types of endometrial adenocarcinomas. They tend to grow and spread faster than most types of endometrial cancer. They often have spread outside the uterus by the time they're diagnosed.
  • endometrial cancers are adenocarcinomas, and endometrioid cancer is the most common type of adenocarcinoma, by far. Endometrioid cancers start in gland cells and look a lot like the normal uterine lining (endometrium). Some of these cancers have squamous cells (squamous cells are flat, thin cells), as well as glandular cells.
  • endometrioid cancers There are many variants (or sub- types) of endometrioid cancers including: Adenocarcinoma, (with squamous differentiation); Adenoacanthoma; Adenosquamous (or mixed cell); Secretory carcinoma; Ciliated carcinoma; Villoglandular adenocarcinoma.
  • Grades 1 and 2 endometrioid cancers are type 1 endometrial cancers. Type 1 cancers are usually not very aggressive and they don't spread to other tissues quickly. Type 1 endometrial cancers are thought to be caused by too much estrogen and sometimes develop from atypical hyperplasia, an abnormal overgrowth of cells in the endometrium. A small number of endometrial cancers are type 2 endometrial cancer.
  • Type 2 cancers are more likely to grow and spread outside the uterus, they have a poorer outlook (than type 1 cancers). Doctors tend to treat these cancers more aggressively. They do not seem to be caused by too much estrogen, i.e., they are not estrogen mediated disease, and thus are often estrogen receptor negative cancers.
  • Type 2 cancers include all endometrial carcinomas that are not type 1, such as papillary serous carcinoma, clear-cell carcinoma, undifferentiated carcinoma, and grade 3 endometrioid carcinoma. These cancers do not look at all like normal endometrium and so are called poorly differentiated or high-grade.
  • Uterine carcinosarcoma (CS) starts in the endometrium and has features of both endometrial carcinoma and sarcoma.
  • CS cancer that starts in muscle cells of the uterus.
  • CS was considered a different type of uterine cancer called uterine sarcoma (see below), but doctors now believe that CS is an endometrial carcinoma that's so abnormal it no longer looks much like the cells it came from (it's poorly differentiated).
  • Uterine CS is a type 2 endometrial carcinoma.
  • CS tumors are also known as malignant mixed mesodermal tumors or malignant mixed mullerian tumors (MMMTs). They make up about 3% of uterine cancers. [0098] Despite the understanding of the major signaling pathways driving the growth and metastasis of endometrial cancer, clinical trials targeting these signals have reported poor outcomes.
  • EC is typically understood to be split into four 20 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 molecular subtypes, including hypermutated cases with POLE mutations and 25-30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR).
  • MSI microsatellite instability
  • dMMR mismatch repair deficiency
  • first line chemotherapy agents have high toxicity profiles and thus have significant co-morbidities associated with their use. Furthermore, being targeted, they sometimes miss the heterogeneous nature of the cancer.
  • first line treatment for EC almost always includes hysterectomy and bilaterial salpingo-oophorectomy. In most cases, this is followed by chemotherapy.
  • a small portion of stage I and II patients may omit or reduce chemotherapy use as compared to Stages III and IV patients.
  • Chemotherapy is virtually always given to stage III or stage IV EC patients, and often with several rounds of therapy, with the goal of optimizing the risks and the rewards.
  • Drugs that are currently utilized for endometrial cancer treatment including but are not limited to paclitaxel, carboplatin, doxorubicin, cisplatin, docetaxel, and the combined therapy of carboplatin or cisplatin with paclitaxel, further agents may also include: altretamine, capecitabine, cyclosphosphamide, etoposide, gemcitabine, ifosfamide, itinotecan, melphalan, pemetrexed, topotecan, binorelbine, fluorouracil, methotrexate, cetuximab, and combinations thereof.
  • Chemotherapy drugs typically fall into different classes of drugs, an alkylating agent, an antimetabolite, ant-tumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, DNA repair enzyme inhibitors, plant alkaloids, and antineoplastics.
  • v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 drugs for EC these fall into the following classes: Paclitaxel is an antineoplastic – plant alkaloid; Docetaxel is an antineoplastic – plant alkaloid; Doxorubicin is an antineoplastic – anthracycline antibiotic; Carboplatin is an antineoplastic – alkylating agent and platinum based; and Cisplatin is an antineoplastic - alkylating agent and platinum based.
  • paclitaxel is given in combination with one or more of cisplatin or carboplatin.
  • platinum-based chemotherapy the majority relapse, and the term “platinum-resistant” refers to patients with EC who progress within six-months of platinum- based therapy. These patients are at the highest risk for disease related mortality. Even with aggressive treatment and especially when not detected until stage III or IV cancer, EC often metastasizes, leading to low survival rates at 2 and 5 years past initial diagnosis and treatment. Because of the risks associated with chemotherapy, including the toxicity to healthy cells as well as the presence of chemoresistant EC, there is a significant need for new therapeutic treatments including ways to reduce or replace chemotherapy.
  • Chemoresistance is defined as simply that the cancer cells are resistant to the action of the particular therapeutic agent, such that the disease progresses. Chemoresistant disease may still have some clinical response, but not at sufficient levels to prevent disease progression, or would require such high doses to make the treatment unsuitable. Chemosensitive, therefore being the opposite, wherein the cancer cells in a patient are sensitive to the chemotherapy agent, so that the disease is managed or reduced. However, EC may be, at one point chemosensitive and then later become chemoresistant as treatment progresses through a typical on/off cycle for chemotherapy. This development confounds clinical treatment in many cases highlighting the need for additional and/or new treatments.
  • Ovarian cancer while originating from different gynecological cells, has significant overlap with endometrial cancer with regard to treatments.
  • the data herein identifies that CBD, alone, or in combination with a chemotherapeutic agent, is effective for treating both of these disease types.
  • other types of estrogen mediated cancers are also known and many have responses that overlap with both endometrial cancer and ovarian cancer. These include, but are not limited to colorectal cancers, breast cancers, noncancerous gynecological diseases, such as ovarian endometrioma, a deep endometriosis, dysmenorrhea, and fibroids.
  • estrogen mediated diseases are frequently treated with an estrogen receptor blocker, or an estrogen 22 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 blocker (to reduce estrogen production), to reduce the total estrogen as a first line therapy.
  • an estrogen receptor blocker or an estrogen 22 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 blocker (to reduce estrogen production), to reduce the total estrogen as a first line therapy.
  • chemotherapy is typically included within this first line therapeutic protocol. What is clear, is that new methods of treatment and new compositions for treatment are urgent needed.
  • Cannabidiol has only recently begun detailed study into therapeutic effects for treatment of disease. Typically, cannabidiol is obtained from a cannabis extract, though it may also be manufactured synthetically.
  • Cannabis extracts can be derived from one or more cannabis plant strains as a source material, or synthetically derived. Leaf and flower from the cannabis plants are extracted to yield the cannabidiol.
  • Cannabis extracts may include isolates of certain compounds, such as isolated CBD, or may include products that contain a wider variety of cannabinoids and other materials, such as those called a full spectrum hemp extract (FSHE) and broad spectrum hemp extract (BSHE), each of which may contain an array of cannabinoids and other phytonutrients such as essential fatty acids, flavonoids, terpenes and essential vitamins and minerals.
  • Cannabinoids are passed into the body by an advanced physiological system, known as the endocannabinoid system (ECS).
  • ECS endocannabinoid system
  • the ECS is widely distributed throughout the entirety of human physiology and is comprised of three main parts. These are: (i) cannabinoid receptors (CB1 and CB2); (ii) endogenous cannabinoids (endocannabinoids) and most notably anandamide and 2-AG; and (iii) Enzymes that break down endocannabinoids (FAAH and MAGL).
  • Cannabinoid receptors found 23 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 on the surface of cells, are widespread throughout the body and listen to the environment around each cell. They transmit information on current conditions to the cell and thereby jump-start the proper cellular response. Properly functioning cannabinoid receptors have the crucial function of creating homeostasis in the body’s cells. [0106] CB1 and CB2 receptors are the predominant receptors in the ECS.
  • CB1 receptors are abundant in the brain and central nervous system, whereas CB2 receptors are sparse in the central nervous system but are common throughout the periphery, primarily on immune cells.
  • Cannabinoid receptors are present in almost every organ and organ system throughout the body. They influence activities in the reproductive system, heart, lungs, brain, blood vessels, GI tract, liver, stomach, and more.
  • Cannabinoids, found in hemp (phytocannabinoids), such as CBD, may influence a wide array of bodily functions. These phytocannabinoids interact with the cannabinoid receptors and modulate their activity – while at the same time boosting levels of endocannabinoids.
  • CBD works with the cannabinoid receptors by inhibiting FAAH (Fatty Acid Amide Hydrolase), an enzyme that breaks down the naturally produced endocannabinoid anandamide, thus prolonging its half-life.
  • FAAH Food Acid Amide Hydrolase
  • Anandamide is partially responsible for regulating human reproduction, among its other implications within the body.
  • cannabinoids exert antiproliferative effects on deep infiltrating endometriosis, and increased cannabinoid signaling may reduce proliferation of endometriotic lesions, the etiology of which shares some genetic basis and pathophysiological overlap with ovarian and endometrial cancers.
  • Cannabinoids trigger localized vasodilation and relaxation of pathological smooth muscle contraction and/or spasticity.
  • Cannabinoid receptors belong to a superfamily of G protein-coupled receptors.
  • CB1 and CB2 cannabinoid receptors are linked to G1/0 proteins.
  • endogenous ligands for these receptors capable of mimicking the pharmacological actions of THC have also been discovered.
  • Such ligands were designated endocannabinoids and included anandamide and 2-arachidonoyl glycerol (2-AG).
  • Anandamide is produced in the brain and peripheral immune tissues such as the spleen.
  • CBD fatty acid amide hydroxylase
  • CBD may be implicated in multiple signaling pathways in the body.
  • CBD may play a modulatory role with regard to cytokines.
  • Cytokines are signaling proteins synthesized and secreted by immune cells upon stimulation. Accordingly, one of the possible mechanisms of immune control by CBD is by perturbing the balance between cytokines produced by T helper subsets, T h 1 and T h 2.
  • T helper subsets T helper subsets
  • both anti-inflammatory and proinflammatory effects were shown.
  • IL-6 suppression can decrease tissue injury.
  • Cannabinoids, including CBD and THC have been shown to decrease IL-6, TNF ⁇ , GM-CSF, and IFN ⁇ .
  • CBD may be a necessary component in certain applications when a combined effect is necessary to reduce inflammation and decrease pain.
  • Low doses of THC may be suitable to provide these therapeutic effects in combination with CBD.
  • CBD is also known to stimulate vanilloid pain receptors (TRPV-1 receptor), which are known to mediate pain perception, inflammation, and body temperature.
  • CBD may also 25 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 impact certain adenosine receptors, which play a significant role in cardiovascular function and broadly impact anti-inflammatory effects throughout the body as well as regulate and decrease anxiety and depression and increase the sense of well-being.
  • THC and CBD are both highly lipophilic and have poor oral bioavailability when swallowed, at between 6 to 10 percent, amounts which may be increased through specific preparations.
  • Oral THC formulations exhibit variable absorption and undergo extensive hepatic first-pass metabolism, resulting in lower peak plasma THC concentration relative to inhalation and a longer onset ( ⁇ 120 min) to reach peak concentration. Following oral administration of CBD, a similar plasma concentration–time profile to that of oral THC has been observed.
  • oral formulations may be useful for patients requiring symptomatic relief over a longer period, though higher concentrations may be necessary, in order to reach therapeutic plasma concentrations, as compared to alternative delivery methods, such as inhalation. Furthermore, certain liver toxicities may exist because of the extensive first pass metabolism when higher dosage amounts are needed for therapeutic levels.
  • Transdermal administration of cannabinoids avoids first-pass metabolism but the extremely hydrophobic nature and high molecular weights of cannabinoids limits diffusion across the aqueous layer of the dermis. This rate limiting step may only be modified by permeation enhancement, or by enhancement or manipulation of the molecule, such as in delivery tools, or as a pro-drug.
  • Effective dermal transport is typically only obtained by permeation enhancement.
  • mucosal transport either through the oral mucosa, nasal mucosa, vaginal mucosa, or rectal mucosa have different properties as compared to the dermal layer, and thus allow for greater diffusion over these tissues.
  • in vitro studies with human skin have determined the permeability potential of CBD to be 10-fold higher than that of ⁇ 9 -THC and ⁇ 8 -THC, consistent with CBD being relatively less lipophilic. This leads to opportunities for CBD for topical administration that are relatively unavailable for ⁇ 9 -THC, and which would be further improved for mucosal administration, which does not contain all of the systemic diffusion challenges of overcoming the barrier function of dermal skin layers.
  • Cannabinoids rapidly distribute into well-vascularized organs (e.g., lung, heart, brain, liver), with subsequent equilibration into less vascularized tissue. Distribution may be affected by body size and composition, and disease states influencing the permeability of blood–tissue barriers. Therefore, when targeting less vascularized organs, the distribution and uptake may be reduced, as compared to other organs. This again points to implications for localized administration for EC treatment, instead of simply through the stomach or oral mucosa as with typical applications of therapeutic treatments.
  • organs e.g., lung, heart, brain, liver
  • CBD is hepatically metabolized, primarily by isozymes CYP450, CYP2C19 and CYP3A4 and additionally, CYP1A1, CYP1A2, CYP2C9 and CYP2D6. After hydroxylation to 7-hydroxy cannabidiol (7-OH-CBD), there is further hepatic metabolism and subsequent fecal, and, to a lesser extent, urinary, excretion of those metabolites. CBD, like THC, has also been reported to have a long terminal elimination half-life, with the average half-life following intravenous dosing observed to be 24 ⁇ 6 hours and post-inhalation to be 31 ⁇ 4 hours.
  • CBD CBD to compete with drugs metabolized through CYP 450 pathways, 27 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 specifically those that interact with enzymes CYP3A4, CYP2C19, and CYP2D6. Dose adjustments may be necessary with substrates of CYP2C8, CYP2C9, CYP2C19, CYP1A2 and CYP2B6.
  • the combination composition provided in the embodiments herein are directed towards the inclusion of CBD and a flavonoid (such as a flavonol or a flavone), each of which may be implicated with one or more of the enzymatic materials listed above, and which may, but Applicant does not limit to such, provide the evidence and rational for the unexpected results of the synergistic combination of the CBD and the flavanoid.
  • a flavonoid such as a flavonol or a flavone
  • Cannabis extracts for therapeutic use in the methods herein are typically generated by an extraction process to remove desired materials from the trichomes and other green material from the hemp plant.
  • Phytocannabinoids are concentrated in a viscous resin that is produced in glandular structures known as trichomes within hemp plants.
  • the resin is rich in terpenes, which are largely responsible for the odor of the plants in the cannabis family. These materials are also present in additional tissues of the plant, most notably in the flowers and leaves of the plants.
  • Phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohol, and nonpolar organic solvents, and can also be suspended in emulsions. For this reason, the prior art often dissolves the cannabinoids into fats and oils, such as vegetable oils. These vegetable oils are highly palpable and can be further flavored to allow for oral administration.
  • the cannabis extracts such as a FSHE or a BSHE further comprise certain amounts of an array of cannabinoids and other phytonutrients such as essential fatty acids, flavonoids, terpenes and essential vitamins and minerals.
  • cannabidiol can also be synthetically manufactured.
  • a representative, nonlimiting sample of the cannabis extract of the present disclosure comprises concentrations of certain compounds within the following ranges: 28 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 [0121] TABLE 1: CANNABINOID EXTRACT EXAMPLES B SHE FSHE % 0 0 0 D D 8 D 5 D 5 5 D 5 0 8 9 0 [0122] Therapeutic treatments comprising CBD and a flavonoid antioxidant.
  • ECC endometrial cancer cells
  • LC liquid chromatography
  • MS/MS tandem mass spectrometry
  • FIG.1C compares the degree to which certain proteins were expressed (or not expressed) in untreated cells and treated cells.
  • FIG.1D of the thousands of proteins that were differentially expressed with treated and untreated cells, the top 20 upregulated (e.g., in treated cells only) and downregulated (e.g., in untreated cells only), are identified and enumerated.
  • FIG.1E the effect of treatment with CE with CBD on signaling and trafficking of various physiological and pathophysiological pathways is shown.
  • FIG. IF and 1G depict that cannabinoid receptors 1 and 2 have significant overlap with regard to the percentage of patients wherein the receptor is implicated in the cancer. Many of these cancers are gynecological, and thus form a significant basis for the determination that use of and treatment of gynecological cancers can be treated with CE comprising CBD.
  • FIG.1H a tissue sample taken from a patient with endometrial cancer was selectively stained to show CB1 receptor expression.
  • FIG.1I is a similar tissue sample selectively stained to show CB2 receptor expression.
  • CBD as a mono therapy or combined therapy towards certain cancerous or estrogen mediated diseased cells.
  • Applicant tested different concentrations of CBD 30 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 in each of the doses with DMSO as the vehicle for all tests.
  • Each of the tests were run in at least triplicate, including the carrier alone. Initial tests started at 250 ⁇ g/mL, which was 100% effective in killing the endometrial cancer organoids.
  • an equivalent CBD dose to a patient of 1 ⁇ g/mL is a dose of approximately 20 mg a day of CBD, 10 ⁇ g/mL is approximately 200 mg a day, 25 ⁇ g/mL is approximately 500 mg a day, and 50 ⁇ g/mL is approximately 1000 mg a day, if provided as a human equivalent dose.
  • the prescribed CBD isolate is given at a dose of between 5 and 50 mg of CBD/kg and in the United States an average weight of between 65 and 85 kg, yields doses of between 325 to 4250 mg a day of CBD. Applicant’s actual tests, therefore, range from well below these doses to about 1 ⁇ 4 of the acceptable dose.
  • grades 1 and 2 EC are ER(+), while grade 3 was ER(-), and whether these different estrogen receptor status would implicate different treatments or different protocols for the greatest efficacy.
  • FIG.2 depicts the results in a graphical form. This was performed for each of grade 1, grade 2 and grade 3 tumors.
  • Grade 1 tumors exhibit 31 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 ⁇ 5% solid nonglandular, nonsquamos growth.
  • Grade 2 EC tumors show between 6% and 50% of solid nonglandular, nonsquamous growth, while grade 3 tumors exhibit >50% of solid nonglandular, nonsquamous growth.
  • FIGS.4A, 4B, 4C, and 4D depict graphical views of concentrations of each of the various different cannabis extracts identified above, at the given concentrations, as tested on endometrial cancer organoids.
  • FIG.4A particularly looks at the BSHE, which replicates prior studies.
  • FIG.4B uses FSHE as the treatment drug
  • FIG.4C uses CBD isolate
  • FIG.4D uses CBDA as the treatment drug.
  • FIG.4A confirms all prior tests
  • the data from FIGS.4B and 4C shows that virtually all patients respond at 7 or 10 ⁇ g/mL, consistent with the results from FIG.4A.
  • CBDA showed an even stronger patient differentiation, wherein even at doses of 10 and 15 ⁇ g/mL, a strong response was not seen in all patient derived organoids. Accordingly, additional dosing up to 50 ⁇ g/mL was completed before all patients showed a nearly 100% reduction in organoid formation.
  • FIG.5 provides for the results of mouse models, which tested the ability of each of the BSHE, FSHE, CBD isolated, and CBDA to inhibit cancerous growth within the mice.
  • first line therapies for gynecological cancers such as those of endometrial cancer and ovarian cancer utilize one of several chemotherapeutic agents.
  • Chemotherapy is often given in progressive doses, meaning, it may take more of the chemotherapy drug to obtain the same response, as disease progresses. In many cases, patients progress wherein the endometrial cancer becomes chemoresistant. Applicant tested the combination of chemotherapy drugs with a cannabis extract to determine if the combination could reduce the amount of chemotherapy required to obtain therapeutic responses, namely reducing the growth of endometrial cancer tumors and ultimately eradicating the tumors. [0135] Several chemotherapeutic agents were tested for efficacy against both organoids and then on mice models.
  • Chemotherapy agents and other current anti-cancer molecules have a typical negative profile, that is, they are highly toxic and kill not just cancer cells, but also healthy cells. Accordingly, a key metric and value is the ability to generate an equivalent clinical response to the chemotherapy, while using a lower total amount of the chemotherapeutic agent.
  • FIG.6A details the use of paclitaxel in combination with CBD.
  • FIG.6A shows a 0 dose (control), meaning only the cannabis extract products, given at an IC50 amount.
  • the IC50 amounts are 3 ⁇ g/mL for the BSHE, 5 ⁇ g/mL for the FSHE and 15 ⁇ g/mL for the CBDA.
  • the paclitaxel is administered at 4 nm/ml and also at 20 nm/ml in combination with the IC50 amount of cannabis extracts.
  • the paclitaxel was also tested at 8, 12, and 16 nm/ml, with only moderate changes in a linear fashion, and are thus not depicted in the drawing.
  • the results for the two different grades of endometrial cancer are generally conserved.
  • the grade 3 cancer which is an ER(-) cancer
  • the grade 2 is ER(+) show slight differences in efficacy.
  • FIG.7 repeats this test with a second chemotherapy drug, carboplatin.
  • FIG.7 like FIG.6A and FIG.6B before, shows IC50 data for four different cannabis extracts.
  • the IC50 data was 5 ⁇ g/mL for the BSHE, 5 ⁇ g/mL for the FSHE, 3 ⁇ g/mL for the CBD, and 15 ⁇ g/mL for the CBDA.
  • each data set has its own IC50, based on how each patient derived organoid responds to a particular agent.
  • the results are generally repeated from the paclitaxel data.
  • Carboplatin has a viability at 50 ⁇ g/mL of only about 50%, virtually equivalent to the IC50 date for all of the CBD.
  • a synergistic effect is seen, where at any dose, the combined effects are superior to either alone.
  • the addition of the cannabis extract with a chemotherapy agent provides for a dramatic reduction in the number of organoids when combined with the paclitaxel or the carboplatin. Accordingly, based on this result, a patient could take a greatly reduced amount of either of the chemotherapy drugs, combined with an effective amount of the cannabis extract comprising CBD to obtain a similar destruction of EC cells, and even shows a much greater impact and higher rate of kill than taking the chemotherapy agent alone, even at the highest effective doses. Furthermore, by testing the most common chemotherapy drugs utilized for EC, one being a plant-based alkaloid and the other a platinum- based, we know that the results are translatable across different chemotherapeutic agents that function in different ways from one another.
  • mice were then grown with EC tumor cells and given a control vehicle, a cannabis extract alone, a chemotherapeutic agent alone, and then a combination of the chemotherapeutic drug (paclitaxel) and the cannabis extract together.
  • the mice were given paclitaxel at 10 mg/kg body weight. This relates to a clinical dose of only 30 mg/m 2 , which is dramatically lower than the 175mg/m 2 that 35 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 is given to human patients.
  • FIG.8 details the results of mice tumor volume comparing paclitaxel alone to those treated with a combined paclitaxel and a cannabis extract. The control, or no treatment is not shown in FIG.8, but results in more than 100% growth over the 21 days, as compared to the initial tumor volume. Combining a low dose of paclitaxel with an effective dose of any of the cannabis extracts yields dramatically greater reduction in tumor volume as compared to the paclitaxel alone or even the cannabis extracts alone at the given dose.
  • mice were sacrificed and histopathology taken to show that treating the mice with cannabis extracts does not damage the cells of the ovary and fallopian tube, the uterus, vagina, or the liver. This is critically important, as treatment with high doses of chemotherapy are indiscriminate and damage these cells, when given over time.
  • the cannabis extract when providing the cannabis extract, especially where the cannabis extract is provided orally, intravaingally or oral mucosally, to utilize a buffer to modify pH to between 2 and 6, yields a superior response, than giving the cannabis extract at its native pH.
  • the cannabis extract is provided in a carrier with a pH of between 3.5 and 5.5, and more preferably at between a pH of between 4 and 5.
  • FIGS.10A and 10B show that ovarian cancer, like endometrial cancer is treated effectively with doses of CE comprising CBD, wherein the CE is a BSHE.
  • FIGS.11A, 11B, 11C, and 11D show individual patient data for BSHE, FSHE, CBD isolate, and CBDA isolate.
  • the results for ovarian cancer replicate the prior surprising finds for endometrial cancer.
  • both chemo sensitive cancer based cells and chemo resistant based organoids were tested.
  • the results were analogous in that the different CEs were able to effectively treat these cancers and dramatically reduce cell viability in all cases.
  • FIGS.12A and 12B depict combination of paclitaxel and CE on ovarian cancer organoids. The results replicate the findings for endometrial cancer. Here, both the chemo resistant and the chemo sensitive cancer derived organoids were more effectively treated with the combination therapy of the paclitaxel and the CE, than either alone.
  • FIGS.13A and 13B depict head and neck cancer organoids response to CE.
  • FIG.14 depicts head and neck cancer organoids response to a combination of paclitaxel and CE. The results confirm the prior results with endometrial cancer and ovarian cancer.
  • FIGS.15A and 15B depict the response of BSHE, FSHE, CBD isolate, and CBDA on endometrial organoids. The results confirm the prior results for other cases for endometrial cancer, ovarian cancer and head and neck cancer.
  • compositions comprising the CE and a flavonoid have therapeutic overlap with those with endometrial cancer.
  • CBD was effective, and surprisingly more effective in combination with a chemotherapeutic agent, or by adjusting pH of the CE to be acidic, variations in treatment were evident in nearly each group of patients.
  • CBD is relatively insoluble in water, it is most frequently provided in an oil, such as an edible vegetable oil.
  • an oil such as an edible vegetable oil.
  • olive oil is olive oil.
  • Olive oil is rich in tocopherol, a known antioxidant.
  • Applicant therefore wanted to test whether dissolving the CE into an oil carrier would support the increased efficacy as described in the prior art.
  • the primary antioxidant, tocopherol was tested for its efficacy on endometrial cancer organoids.
  • the tocopherol was administered in DMSO as the carrier to the endometrial cancer cells. Despite its widespread use in the prior art, the tocopherol had virtually no impact on cell viability when used alone in the carrier. Indeed, if anything, it was responsible for cell proliferation, as depicted in FIG.16, as compared to the carrier alone. [0155] In view of the result, Applicant wanted to see if this was conserved among other antioxidants.
  • Applicant obtained beta-caryophyllene, another potent antioxidant with a significantly different structure than the tocopherol, as well as three other molecules, each of which are closely related flavonoids, these being myricetin, taxifolin, and chrysin.
  • Flavonols are a class of compounds having a 3-hydroxyflavone backbone, and which additional members of the genus differ based upon the different positions of the phenolic bydroxyl groups. Each were tested at concentrations equivalent to those tested above for tocopherol.
  • the flavonol class of compounds are inhibitors of CYP2C9 and CYP3A4, which are known to metabolize drugs in the body, including cannabidiol.
  • FIG.17A and 17B compare several of the selected antioxidants in combination with BSHE.
  • FIG.17A first compares tocopherol, beta-caryophyllene, and taxifolin in combination with BSHE at an IC50.
  • the combination with a BSHE showed some promise for each of these molecules, however, their concentrations typically requiring at least a 25 micromolar or higher concentration, when combined with the IC50 of the BSHE to show significant variance from the IC50 value.
  • each of the materials showed an unexpected potential for its combined efficacy with the BSHE.
  • v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 referring back to FIG.16, each of those three materials, at a concentration of 50 ⁇ M, and virtually at 75 ⁇ M were inducing cell proliferation.
  • FIG.17B depicts the response of myrecetin and chrysin, when combined with the IC50 of the BSHE, each of which are most similar in structure to taxifolin. Note that at a concentration as low as 12.5 ⁇ M, each of the materials showed nearly 0% cell viability.
  • chrysin was a weak performer, and actually inducing cell growth at lower concentrations, and only showing any sign of efficacy at above about 75 ⁇ M in concentration.
  • chrysin was most effective at a range of between about 75 and 150 ⁇ M, and actually performed worse at a concentration above 150 ⁇ M, and showing at 10 ⁇ M a growth of 178.99, at 25 ⁇ M a growth of 188.45, and at 50 ⁇ M a growth of 125.21%.
  • 100 ⁇ M however, it had reduced viability to 56.74, about at in IC50 amount.
  • FIG.18 then performs the same test as in FIG.17A and 17B just with a FSHE, to see if the results were conserved. Generally, myricetin showed a similar efficacy, while tocopherol essentially made the IC50 FSHE ineffective, and confirming that it should be avoided in combination with a cannabis extract.
  • Taxifolin was ineffective until at a higher concentration of about 45 ⁇ M, while others were somewhat more effective at concentrations below 20 and 41 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 remained fairly stable through higher concentrations. Chrysin, maintained its efficacy improvements as seen with the BSHE test, and was generally the 2 nd most effective combination after the myricetin.
  • myricetin showed a significant synergy when used with either a BSHE or a FSHE, while other flavanols, flavononol, or flavone also showed unexpected synergy at slightly higher levels, but each of these flavonoids showed a greatly unexpected synergy in combination with either of the cannabis extracts, which was wholly unexpected based on their monotherapy response. Accordingly, looking at the structure of myricetin, it has a higher number of hydroxyl groups on the phenol ring, as compared to either chrysin or taxifolin.
  • chrysin has no hydroxyl groups on the phenol ring
  • taxifolin is a flavanonol, having the phenolic ring as a chiral center. Except for the chiral nature, taxifolin differs from myricetin only as to omitting one hydroxyl group attached at the 3′ position on the Phenol ring (also called R3′) herein as provided in the generic structure below.
  • the composition is a flavonol, which has the following structure: [0166]
  • the R3 the prior structure in the substitution of the hydroxyl group at this position.
  • the flavonol comprises at least one hydroxyl group attached at one of R5, R6, R7, R8, R2′, R3′, R4′, or R5′.
  • the flavonol has a hydroxyl group attached at R5 and R7, and at least two of R2′, R3′, R4′, R5′, and R6′, with the remaining being a hydrogen.
  • the flavonols tested at two flavone molecules, luteolin and chrysin both showed therapeutic efficacy.
  • v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 particular, treatment of endometriosis organoids confirms that treatment shall be effective in not only the endometrial cancer and ovarian cancer, but also to these noncancerous gynecological disease states such as: ovarian endometrioma, a deep endometriosis, dysmenorrhea, and fibroids. Indeed, it is postulated that the synergy may be implicated in part based on the estrogen dominance of most of these cancers and would support that other such estrogen sensitive or dominant diseases would also be effectively treated by these unexpected compositions.
  • the data shows an unexpected synergy towards the inclusion of one or more of certain classes of flavonoid antioxidants, while simultaneously, showing that certain molecules should be avoided. Most notably of these is that tocopherol should be excluded from formulations.
  • This finding is profoundly unexpected, as the literature includes numerous citations in which carriers which are known to be high in tocopherol (for example, olive oil) are suggested to be used as the carrier, or as part of an oil in water emulsion. See US patent pub No. 2023/0090094 Hemp extract for treatment of pain, cancer and epilepsy in animals (Kjaer, et al.) or CA3020798A1 Ingestible films having substances from hemp or cannabis (Schaneville).
  • Applicant’s results show something that is otherwise completely unexpected.
  • the presence of one or more flavonoids, in combination with CBD yields dramatic synergy towards killing cancerous cells as well as noncancerous disease. Therefore, a composition comprising CBD and one of more flavonoid is effective for treatment of the various gynecological cancers, estrogen mediated diseases, and noncancerous gynecological disorders.
  • the flavonoid is a flavonol.
  • the flavonoid is a flavonol, a flavononol, or a flavone.
  • compositions comprising CBD and a flavonoid, and particularly to flavonol, flavononols, or flavones are effective at treating several gynecological diseases, including estrogen mediated disease, estrogen receptor + disease, and certain nongynecological diseases including ovarian endometrioma, a deep endometriosis, dysmenorrhea, and fibroids.
  • the compositions can be effectively utilized in one or more methods of treatment comprising administering to a patient in need thereof, of an effective amount of the composition to treat one or more of the disease states.
  • the composition can also be further provided in combination with a chemotherapeutic agent, wherein the combination of therapy can be utilized for treatment of endometrial cancer, ovarian cancer, and/or one or more estrogen mediated cancers.
  • a method of treating a grade 1, 2, or 3 gynecological cancer comprising administering to a patient in need thereof, an effective amount of a composition comprising a cannabis extract comprising CBD, and a flavonol.
  • the cannabis extract comprises total cannabinoids of between 50 and 99.9 of the cannabis extract.
  • the percent of the cannabis extract means that, as in the preceding sentence the total cannabinoids make up between 50 and 99.9% by weight of the cannabis extract.
  • CBD makes up at least 60%, and more preferably, at least 65, 70, 75, 80, 85, 90, 95, and 99% of all cannabinoids within a cannabis extract.
  • a dose is provided as an oromucosal dose, an intravaginal dose, a nasal mucosal dose, a rectal dose, an oral dose, an intramuscular injection, or an intravenous dose.
  • Another patient with Stage IIIc, high grade serous ovarian cancer was BRCA Negative.
  • Two additional patients, one with Stage IVc, low grade serous ovarian cancer and one with undefined ovarian cancer did not have mutations noted.
  • BRCA2, and TP53 are commonly conserved mutations being susceptible to the ovarian cancer in these patient lines, and whose organoids were then successfully treated with either of the cannabis extract alone or concurrently with one or more chemotherapeutic agent.
  • a preferred embodiment is related to a method of treatment of a gynecological cancer comprising administering to a patient an effective amount of a pharmaceutically acceptably composition comprising a cannabis extract having between 50 and 100% by weight CBD, wherein the composition comprises one of a BSHE, a FSHE, a CBD isolate or CBDA as the CBD source and an antioxidant, which is a flavonol.
  • the composition is substantially free of a tocopherol (having less than 0.1 weight percent of the composition).
  • the composition is completely free of a tocopherol (being present at a level below the limits of detection).
  • an effective dose is between 10 and 2500 mg a day of CBD.
  • it may be suitable to co-administer the CBD treatment with an ongoing radiation or chemotherapeutic treatment.
  • Therapeutic coadministration may be suitable for increasing efficacy and/or decreasing the dose and thus toxicity related to chemotherapeutic treatment.
  • it is advantageous to modify the osmolality of the composition for therapeutic administration so as to be gentle for intravaginal bacteria by the addition of one or more common salts.
  • PH of the carrier it may be appropriate to modify the PH of the carrier so as to more appropriately match the pH of the vagina, which is typically acidic.
  • a buffer comprising the appropriate conjungate acid and base pair can be utilized to select and maintain an appropriate pH.
  • oral mucosal administration or intravaginal administration of the compositions are provided at a pH of between 2 and 6 and most preferably at between 3.5 and 6.
  • RESULTS Hank’s Balanced Salt Solution
  • P/S Pencillin/Streptomycin
  • the filter was removed, and the flow- through with the cells was collected in 5% FBS AD+++ medium (comprising 1% ITS, 2% B27, 1% N2, 25% WRN, hegf-50 ng/mL, hfgf-10-100 ng/mL, Nicotinamide-1mM, N-acetyl cysteine- 1.25mM, Primocin-0.2%, Estrogen-2nm, A8301-0.5 ⁇ M, and Y27632 ).
  • This cell suspension was centrifuged at 1000 rpm for 5 minutes at room temperature to get the cell pellet for counting. Upon checking under hemocytometer cell number was calculated and processed for organoid culture.
  • PROTOCOL FOR ALL TESTS PATIENT-DERIVED ORGANOID (PDO) CULTURE AND DRUG TREATMENT
  • 2-3x10 ⁇ 3 cells were plated in a pre-warmed (37°C) 96-well plate in 10 mL of Matrigel (5% FBS AD+++ medium) per well. Individual patient cell organoid was cultured separately in different plates. Individual patient cells were handled separately to reduce the chance of cross-contamination. After mixing cells with Matrigel, 10 mL droplets were placed in wells and put in a 37°C incubator with 5% CO2 for 30 minutes.
  • the plate Upon solidification of the Matrigel droplet with cells inside, the plate was placed inside a sterile hood and immersed the Matrigel droplet in 200 ⁇ L of organoid growth media. Cells were allowed to grow into mature organoids for 14 days. Treatment with individual CBD agents (Broad Spectrum, Full Spectrum, CBD Isolates, and CBDA) or in combination with 48 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 chemotherapeutic agents (Paclitaxel, Doxorubicin or Carboplatin) was started from day 1, where the individual drug or drug combinations were added in the growth medium.
  • CBD agents Broad Spectrum, Full Spectrum, CBD Isolates, and CBDA
  • chemotherapeutic agents Paclitaxel, Doxorubicin or Carboplatin
  • IC50 specific dose
  • chemotherapeutic agents Paclitaxel, Doxorubicin or Carboplatin
  • IC50 is the 50% inhibitory concentration which is conventionally used to determine drug potency with cell-based cytotoxicity tests.
  • all of the antioxidants were tested under the same protocol.
  • the matrigel droplet in each well with organoid inside was immersed in 100 ⁇ L of fresh growth media and 100 ⁇ L of CellTiter-Glo ® reagent following the manufacturer’s guideline. Blank wells containing only media and CellTiter Glo ® reagent (no cells) were also included in each plate. Then the plates were put on a shaker at 110 RPM at room temperature for 5 minutes to induce cell lysis, followed by 25 minutes at room temperature to stabilize the luminescent signal. Each step after adding the CellTiter Glo® reagent was performed in the dark. Luminescence was measured on a FLUOstar OPTIMA plate reader (BMG Lab technologies, Offenburg, Germany).
  • mice were intraperitoneally injected with CBD single agents (all 10-30 mg/kg body wt) and/or CBD + chemotherapeutics (CBD (10-30mg/kg body wt), Paclitaxel (up to 20mg/kg body wt)/ Carboplatin (up to 60mg/kg body wt), Doxorubicin (up to 15mg/kg body wt)) or Vehicle thrice per week for up to 5 weeks. Tumor size measured before treatment, followed by twice a week measurement. All treatment group mice were kept alive for up to 10 weeks after drug injection or until the tumor volume grows bigger than 2500mm 3 . [0190] Tumor size was measured along with body weight at the time of tissue collection.
  • CBD chemotherapeutics
  • Paclitaxel up to 20mg/kg body wt
  • Carboplatin up to 60mg/kg body wt
  • Doxorubicin up to 15mg/kg body wt
  • Vehicle thrice per week for
  • samples tested in 96 well plates can use a different formula for translating to human dosage.
  • the surface area of a single well in 96 well plates is 0.32 cm 2 .
  • Clinical Dosage (mg/m 2 ) (PDO dosage in mg/culture plate surface area cm 2 ) x 100 2 .
  • Clinical Dosage (mg/m 2 ) (PDO dosage in mg/culture plate surface area cm 2 ) x 100 2 .
  • Dosing was 30 mg/kg of each of the cannabis extracts, the results of the CBD only study is defined in FIG.5.
  • the concentration of CBD used in each case remains on the low end of the therapeutic dose suitable for administering to a human patient, or to a mouse.
  • the low doses were utilized in order to show impact of the cannabis extracts, instead of each of the data going to zero, by using double, triple, or higher of the dose as administered to the mice, all of which would be appropriate human equivalent doses.
  • compositions and materials namely comprising a cannabis extract and a flavonoid is identified to produce an unexpected synergistic response towards destruction of diseased cells, specifically towards certain noncancerous gynecological cells or lesions, as well as towards cancerous lesions, solid tumor cancers, and specifically those of endometrial cancer and ovarian cancer.
  • Delivery mechanisms are provided for delivering the active therapeutic ingredients to a patient.
  • gynecological tissues can be targeted by certain applications, whether through oral, oral mucosal, vaginal mucosal, or other administration to treat gynecological tumors, and reduce tumor size through treatment with cannabis extracts comprising CBD. Because of the targeted approach towards gynecological tissues, those of ordinary skill in the art will recognize that certain therapeutics are able to pass through the vaginal mucosa and contact tissues both on the vaginal wall, but also tissues adjacent to the vaginal wall, including the entirety of the gynecological tract, including the uterus, cervix, ovaries, etc., as nonlimiting tissues.
  • Intravaginal delivery is well studied and considered safe, effective and well tolerated. Intravaginal delivery avoids gastrointestinal absorption and bypasses first pass metabolism, while facilitating a localized effect and a steady, sustained therapeutic response.
  • vaginal epithelium Absorption and systemic delivery via vaginal epithelium occurs rapidly with similar lipophilic compounds. Variances in thickness of the vaginal epithelium and vagina fluid characteristics, including pH, presence of cervical mucous, and microbiota, may influence absorption rates and bioavailability. [0200] Accordingly, mucosal dosing, particularly intravaginal dosing has a therapeutic efficacy that can allow for targeted treatment of EC cells, which will treat both localized tumors 52 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 as well as metastasized tumors.
  • Full spectrum hemp extract, broad spectrum hemp extract, CBD isolate, and CBDA isolate are forms of cannabis extract utilized herein, as nonlimiting examples of the CE.
  • CBD is often used interchangeably with CE, to mean the CE product containing the particular amount of CBD.
  • the CBD refers to a CBD isolate, which means the CE was processed to remove and isolate CBD, removing virtually all other components of the CE.
  • CEs in combination with a flavonoid was unexpectedly synergistic and provides for a new therapeutic opportunity for treatment of these and other disease and disorders.
  • Mucosal dosing may be easily administered through the oral mucosa. Data on oral- mucosal or sublingual delivery, demonstrates that CBD has a maximum plasma concentration of 1.6 hours, but this can be delayed in some individuals. Orally delivered CBD has a maximum plasma concentration of about 2.5-5 hours but can be delayed up to 6 hours for some individuals.
  • Rectal suppository delivery results in an increased bioavailability (51-60%) versus oral routes for CBD. Accordingly, mucosal dosing, can allow for targeted administration of cannabis extracts to treat both local and also metastatic tumors. Additional dosing may still be accomplished via 53 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 traditional dosing routes, including but not limited to oral dosage forms, such as a soft gel comprising a cannabis extract. Furthermore, administration may be injected, intramuscularly, or into other suitable tissues for uptake.
  • mucosal dosing particularly intravaginal dosing has a therapeutic efficacy that can allow for targeted treatment of NCGD, and gynecological cancer cells.
  • These therapeutic compositions and methods will treat both localized lesions or tumors as well as metastasized tumors in diseases such as ovarian cancer and endometrial cancer.
  • These data were confirmed by further testing within human patients, which showed that treatment with CBD was effective in reducing chemoresistant EC, which had metastasized, in the body.
  • a composition comprises a CE and at least one flavonoid.
  • the flavonoid is a flavonol, a flavone or a flavononol, and most preferably comprising at least one hydroxyl group, and most preferably at least two hydroxyl groups at R5, R6, R7, R8, and R2′, R3′, R4′, and R5′.
  • the composition for mucosal administration comprises a carrier.
  • the composition further comprises one or more mucoadhesive compounds.
  • the composition further comprises one or more stabilizers.
  • the composition further comprises one or more flowing agents, bulking agents, and a buffer.
  • the composition may also comprise a chemotherapeutic agent.
  • the composition may include the CE, and a second composition comprises the flavonoid, and/or a chemotherapeutic agent, or even a third composition comprising the flavonoid and/or the chemotherapeutic agent.
  • the composition is buffered to be acidic, when administered to the mucosal surface. Wherein the acidic pH at between 2 and 6, and preferably between 3.5 and 6, and most preferably between 4 and 5, increases the efficacy of the composition, as compared to buffering at 10.5, or about the native pH of the CE without a carrier or buffer added thereto.
  • the CE comprises a FSHE or a BSHE.
  • the FSHE or the BSHE are purified extracts comprising two or more cannabinoids.
  • the composition is formulated with at least 1 – 10% CBDA.
  • CBDA is reported to increase the bioavailability of CBD.
  • the CBDA being in an acid form, also includes a stabilizing agent to prevent the oxidation of the CBDA to CBD.
  • the 54 4878-7559-0508, v.4 STABILIZED COMPOSITIONS COMPRISING CANNABIDIOL PATENT DOCKET No.: ECO01.0022.500 antioxidant, as the flavonol may be included at between 0.1 and 10%.
  • the combination of CBD and CBDA allows for an increase in the rate of absorption of both the CBDA and the CBD, thus increasing the efficacy of the composition as a whole.
  • the embodiments and illustrations described herein are provided by way of example and that the present invention is not limited to what has been particularly disclosed. Rather, the scope of the present invention includes both combinations and sub combinations of the various features described above, as well as variations and modifications thereof that would occur to persons skilled in the art upon reading the forgoing description and that are not disclosed in the prior art. Therefore, the various compositions and methods may include one or all of the limitations of an embodiment, be performed in any order, or may combine limitations from different embodiments, as would be understood by those implementing the various methods and systems detailed herein. 55 4878-7559-0508, v.4

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Abstract

La présente invention concerne des compositions et des méthodes d'utilisation pour le traitement d'un ou de plusieurs troubles parmi les suivants : le cancer de l'ovaire, le cancer de l'endomètre, le cancer de la tête et du cou, des troubles gynécologiques non cancéreux et des cancers sensibles aux œstrogènes, la composition comprenant une quantité efficace d'un cannabinoïde et d'un flavonoïde, la méthode comprenant l'administration à un patient en ayant besoin d'une quantité efficace de la composition et éventuellement l'administration de la composition de manière concomitante avec un agent chimiothérapeutique.
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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3020798A1 (fr) 2016-04-12 2017-10-19 Scott SCHANEVILLE Films a ingerer contenant des substances provenant du chanvre ou du cannabis
WO2019222459A1 (fr) * 2018-05-18 2019-11-21 Diverse Biotech, Inc. Préparations de cannabinoïdes et utilisations thérapeutiques
WO2020163775A1 (fr) 2019-02-08 2020-08-13 Srin Therapeutics, Inc. Compositions cannabinoïdes et leurs procédés d'utilisation pour la modulation immunitaire, la protection immunitaire et le traitement du cancer
WO2020194237A1 (fr) 2019-03-28 2020-10-01 Scicann Therapeutics Inc. Compositions de cannabinoïdes et leur utilisation
US20210068444A1 (en) * 2019-09-10 2021-03-11 California Amber Inc. Cannabinoid compositions with improved organoleptic and therapeutic properties, method of production, and use thereof
US20220062224A1 (en) * 2020-08-25 2022-03-03 Brilliant Lab LLC Supplement that enhances intracellular concentration of bioactive molecules through inhibition of multidrug resistant (mdr) efflux pumps
WO2022144878A1 (fr) * 2020-12-28 2022-07-07 Technion Research And Development Foundation Limited Cannabinoïdes et leurs utilisations pour le traitement de maladies associées aux récepteurs des oestrogènes
WO2022165349A1 (fr) * 2021-01-29 2022-08-04 The Johns Hopkins University Distributeur de pilules intelligent
US20220253919A1 (en) * 2021-02-09 2022-08-11 Marcus DENNER Method for generating an electronic offer list
US20230090094A1 (en) 2019-07-02 2023-03-23 Ellevet Sciences Hemp extract for treatment of pain, cancer and epilepsy in animals

Family Cites Families (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2460672B (en) 2008-06-04 2012-01-04 Gw Pharma Ltd Cannabinoids in combination with non-cannabinoid chemotherapeutic agents that are alkylating agents
MX2011011514A (es) 2009-04-28 2011-11-18 Alltranz Inc Formulaciones de canabidiol y metodos para utilizarlas.
GB2478595B (en) 2010-03-12 2018-04-04 Gw Pharma Ltd Phytocannabinoids in the treatment of glioma
US20150126754A1 (en) 2012-05-03 2015-05-07 Echo Pharmaceuticals B.V. Cannabis plant isolate comprising delta-9-tetrahydrocannabinol and a method for preparing such an isolate
EP2719375A1 (fr) 2012-10-10 2014-04-16 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Cannabinoïdes pour le traitement de cancers liés au mécanisme hedgehog
GB2515312A (en) 2013-06-19 2014-12-24 Gw Pharma Ltd The use of phytocannabinoids in the treatment of ovarian carcinoma
GB2527590A (en) 2014-06-27 2015-12-30 Otsuka Pharma Co Ltd Active pharmaceutical ingredient (API) comprising cannabinoids for use in the treatment of cancer
US20170189373A1 (en) 2015-05-15 2017-07-06 Andrew Hospodor Terpene Control in Scaleable Cannabinoid Medicinal Formulations
BG112018A (bg) 2015-05-22 2016-11-30 "Побелч-Гле" Оод Метод за получаване на канабиноиден извлек от коноп
US11090275B2 (en) 2015-10-27 2021-08-17 Jay Pharma Inc. Compositions comprising cannabidiol and second therapeutic agents for the treatment of cancer
US20220054429A1 (en) 2015-10-27 2022-02-24 Jay Pharma, Inc. Compositions comprising cannabidiol and second therapeutic agents for the treatment of cancer
US10814248B2 (en) 2016-04-14 2020-10-27 Capna Ip Capital, Llc Methods to reduce chlorophyll co-extraction through extraction of select moieties essential oils and aromatic isolates
US10940136B2 (en) 2016-11-24 2021-03-09 Aop Orphan Pharmaceuticals Ag Cannabinoids for prophylactic treatment of involuntary weight loss
WO2018167038A1 (fr) 2017-03-15 2018-09-20 Aalborg Universitet Procédé d'extraction de cannabinoïdes à partir d'une matière végétale de cannabis
CA3068383A1 (fr) 2017-06-28 2019-01-03 Buzzelet Development And Technologies Ltd. Produit cannabinoide enrichi en terpene bon pour la sante des femmes
CN109394836A (zh) 2017-08-18 2019-03-01 汉义生物科技（北京）有限公司 一种预防和/或缓解痛经的大麻纤维及其在卫生用品中的应用
WO2019043679A1 (fr) 2017-09-04 2019-03-07 Cannabics Pharmaceuticals Inc. Procédé d'analyse de sensibilité des cannabinoïdes sur des biopsies tumorales et des ctc dérivées d'un patient
EP3449992A1 (fr) 2017-09-04 2019-03-06 Bionorica Ethics GmbH Récupération de cannabinoïdes acides à partir de matière végétale
CN109498606A (zh) 2017-09-15 2019-03-22 汉义生物科技（北京）有限公司 一种含有大麻二酚和/或次大麻二酚的组合物及其在治疗痛经中的应用
CA3116187A1 (fr) 2017-11-29 2019-06-06 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Compositions de cannabinoides et methodes
WO2019145552A1 (fr) 2018-01-29 2019-08-01 Phytoplant Research S.L Procédés de purification de cannabinoïdes par chromatographie liquide : liquide
CN108433880A (zh) 2018-03-19 2018-08-24 烟台汉麻生物技术有限公司 一种汉麻卫生巾
US11020357B2 (en) 2018-03-19 2021-06-01 Alexandra Yerike Compound for use in relief of pain and method to produce thereof
WO2019195943A1 (fr) 2018-04-13 2019-10-17 Urban Juve Provisions Inc. Extrait de racine de cannabis, procédé de fabrication, procédé d'utilisation
US20200063202A1 (en) 2018-04-25 2020-02-27 Juneau Biosciences, L.L.C. Methods of using genetic markers associated with endometriosis
GB201806953D0 (en) 2018-04-27 2018-06-13 Gw Res Ltd Cannabidiol Preparations
WO2020097358A1 (fr) 2018-11-07 2020-05-14 Columbia Care, Llc Formulations de suppositoire ayant un cannabinoïde
US20220151978A1 (en) 2019-02-17 2022-05-19 Buzzelet Development And Technologies Ltd. A kit for treating pelvic pain arising from female reproductive system
WO2020183455A1 (fr) 2019-03-10 2020-09-17 Bol Pharma Ltd. Combinaisons de cannabinoïdes pour le traitement des douleurs lombaires
GB201903546D0 (en) 2019-03-15 2019-05-01 Ldn Pharma Ltd Cancer treatment
US20220168238A1 (en) 2019-04-09 2022-06-02 Village Flora, Inc. Methods and compositions for use in treatment of cancer without psychoactive effects
US20230248747A1 (en) 2019-04-30 2023-08-10 Greenway Herbal Products, Llc Cannabinoid and omega fatty acid compositions and methods of using
US20230015268A1 (en) 2019-04-30 2023-01-19 Greenway Herbal Products, Llc Cannabinoid and omega fatty acid compositions and methods of using
WO2020223510A1 (fr) 2019-04-30 2020-11-05 Greenway Herbal Products, Llc Compositions de cannabinoïdes et procédés d'utilisation
CN110063953A (zh) 2019-05-30 2019-07-30 栾云鹏 一种治疗子宫内膜癌的药物组合物
WO2021011790A1 (fr) 2019-07-16 2021-01-21 Advanced Female Technologies Llc Compositions de gomme à mâcher pour le traitement de la douleur menstruelle
US20230002340A1 (en) 2019-07-31 2023-01-05 Canopy Growth Corporation Separation of cannabinoids from mixtures thereof by distillation
WO2021028646A1 (fr) 2019-08-09 2021-02-18 Jay Pharma Inc. Régimes d'administration de cannabinoïdes combinés à des agents chimiothérapeutiques contre le cancer
US20210128521A1 (en) 2019-10-30 2021-05-06 Precision Biologics Methods of using cannabinoid compositions in sports medicine applications
US20210145764A1 (en) 2019-11-15 2021-05-20 Brigham Young University Compositions of cannabidiol (cbd), and/or polyphenols, and methods for the prevention and/or treatment of skin, muscle, nerve and inflammatory disorders, and biological factors and functions in mammals
GB201916960D0 (en) 2019-11-21 2020-01-08 Vitus Group As Compositions
EP4081208A4 (fr) 2019-12-28 2024-01-03 Buzzelet Development And Technologies Ltd Compositions liquides comprenant des terpènes et des cannabinoïdes
AU2020427201A1 (en) 2020-02-07 2022-08-25 Desert Harvest, Inc. Novel cannabinoid carrier compositions having enhance pharmacokinetic properties and methods of use thereof
RU2745687C1 (ru) 2020-05-19 2021-03-30 Всеволод Иванович Киселев Способ лечения эндометриоза с болевым синдромом и фармацевтическая композиция для его реализации
WO2021240510A1 (fr) 2020-05-24 2021-12-02 Asana Bio Group Ltd. Compositions de cannabinoïdes et leurs méthodes d'utilisation
WO2021245522A1 (fr) 2020-05-31 2021-12-09 Buzzelet Development And Technologies Ltd. Compositions de cannabis liquides et leurs utilisations
WO2022011393A1 (fr) * 2020-07-08 2022-01-13 Shaman Naturals, Llc Compositions pour la prévention et le traitement du diabète
IL276051B (en) 2020-07-14 2021-04-29 Cannassure Ltd Oral cannabinoid compositions
CA3185514A1 (fr) 2020-07-17 2022-01-20 Ramachandra MUKUNDA Composition a base de cannabidiol (cbd) et methode de traitement de la douleur
US20230321167A1 (en) 2020-07-21 2023-10-12 Apollon Formularies Plc Compositions and methods for treatment of cancers
WO2022105952A1 (fr) 2020-11-19 2022-05-27 Cb21 Pharma, S.R.O. Composition pharmaceutique
AU2021393122A1 (en) 2020-12-03 2023-06-29 Pike Therapeutics Inc. Transdermal pharmaceutical formulations comprising cbd or thc for the treatment of cancer
US20240091292A1 (en) 2021-02-01 2024-03-21 Apollon Formularies Plc Methods for treatment of human cancers using cannabis compositions
US20220313623A1 (en) * 2021-03-25 2022-10-06 Pet Releaf Ip, Llc Cannabinoid formulation and method of making thereof
WO2022215071A1 (fr) 2021-04-05 2022-10-13 The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Institute) Compositions et procédés pour le traitement du cancer
US12029719B2 (en) 2021-04-16 2024-07-09 Allen Morgan Compounds comprising cannabinoids and other natural ingredients for alieving premenstrual, menstrual and menopausal symptoms
CA3214348A1 (fr) 2021-04-19 2022-10-27 Anahid Jewett Limitation de la croissance de cellules souches cancereuses par le cannabis dans des cancers peu differencies
US20240299424A1 (en) 2021-07-12 2024-09-12 Integrative Therapy Discovery Lab S.R.L. Use of phytocannabinoids for treating endometrial cancer and endometriosis
US20240148759A1 (en) 2021-08-03 2024-05-09 Pebble Global Holdings Non-Psychoactive Multi-Cannabinoid And Terpene-Based Therapeutic Compositions And Methods Of Their Administration
WO2023062634A1 (fr) 2021-10-13 2023-04-20 G.R.I.N Ultra Ltd Compositions comprenant des cannabinoïdes et leurs méthodes d'utilisation dans le traitement du cancer
CA3235080A1 (fr) 2021-10-26 2023-04-05 Alexandra M CAPANO Methodes de traitement de l'endometriose et d'autres troubles gynecologiques non cancereux avec un extrait de chanvre
CA3235074A1 (fr) 2021-10-26 2023-05-04 Alexandra M CAPANO Methodes de traitement du cancer de l'ovaire par un extrait de chanvre

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3020798A1 (fr) 2016-04-12 2017-10-19 Scott SCHANEVILLE Films a ingerer contenant des substances provenant du chanvre ou du cannabis
WO2019222459A1 (fr) * 2018-05-18 2019-11-21 Diverse Biotech, Inc. Préparations de cannabinoïdes et utilisations thérapeutiques
WO2020163775A1 (fr) 2019-02-08 2020-08-13 Srin Therapeutics, Inc. Compositions cannabinoïdes et leurs procédés d'utilisation pour la modulation immunitaire, la protection immunitaire et le traitement du cancer
WO2020194237A1 (fr) 2019-03-28 2020-10-01 Scicann Therapeutics Inc. Compositions de cannabinoïdes et leur utilisation
US20230090094A1 (en) 2019-07-02 2023-03-23 Ellevet Sciences Hemp extract for treatment of pain, cancer and epilepsy in animals
US20210068444A1 (en) * 2019-09-10 2021-03-11 California Amber Inc. Cannabinoid compositions with improved organoleptic and therapeutic properties, method of production, and use thereof
US20220062224A1 (en) * 2020-08-25 2022-03-03 Brilliant Lab LLC Supplement that enhances intracellular concentration of bioactive molecules through inhibition of multidrug resistant (mdr) efflux pumps
WO2022144878A1 (fr) * 2020-12-28 2022-07-07 Technion Research And Development Foundation Limited Cannabinoïdes et leurs utilisations pour le traitement de maladies associées aux récepteurs des oestrogènes
WO2022165349A1 (fr) * 2021-01-29 2022-08-04 The Johns Hopkins University Distributeur de pilules intelligent
US20220253919A1 (en) * 2021-02-09 2022-08-11 Marcus DENNER Method for generating an electronic offer list

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FONSECA B M ET AL: "Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis", JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY, SPRINGER NETHERLANDS, NL, vol. 74, no. 2, 13 February 2018 (2018-02-13), pages 261 - 272, XP037055297, ISSN: 1138-7548, [retrieved on 20180213], DOI: 10.1007/S13105-018-0611-7 *

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